Substance use disorders (SUDs; alcohol and drug abuse and dependence) are associated with substantial negative outcomes and significant impairment in multiple domains of functioning, including physical health and mortality, psychiatric health, psychosocial functioning, and neurocognitive deficits. SUDs are also associated with structural and functional brain deviations. However, the primarily cross-sectional nature of the vast majority of existing research means that the causal basis of these associations remains unclear: substance misuse appears to have neurotoxic effects on the brain, but it is also plausible that premorbid brain deviations that precede substance use influence the development of both SUDs and related impairment. The aims of the proposed career development award are twofold: (1) to train the candidate in pediatric neuroimaging techniques, including magnetic resonance imaging (MRI), diffusion tensor imaging (DTI), and resting state connectivity MRI, for assessing brain structure and functioning during key developmental periods; and (2) to use this training to examine brain structure in young children at high and low risk for the development of problematic substance use using an innovative and powerful offspring of monozygotic (MZ) co- twin control study design that disentangles genetic and environmental effects on the developing brain. The candidate will receive training essential for her development as an independent research scientist under the guidance of an outstanding team of mentors with extensive expertise in substance use, brain development, pediatric neuroimaging, and behavioral genetics (Drs. William Iacono, Kathleen Thomas, Matt McGue, Irving Gottesman). This training builds upon the candidate's already strong scientific background and will ensure that she is well situated to launch an independent research career and make substantive contributions to the substance use literature. The research will be conducted at the Minnesota Center for Twin and Family Research (MCTFR), which offers unparalleled opportunities for applying genetically informative study designs to examine genetic and environmental influences on substance use in several large, population-based cohorts of twins, prospectively assessed from preadolescence into middle age. Two specific aims will be addressed in a sample of 120 7- to 11-year-old offspring of these twins: (1) examine brain structure in offspring at high and low risk for SUDs with the aim of identifying premorbid brain deviations associated with risk; and (2) determine whether brain deviations reflect preexisting liability for substance misuse or instead reflect offspring exposure to a rearing environment associated with having a SUDs-affected parent. Results of the proposed project have great potential to further understanding of the etiology and consequences of SUDs, and, in turn, guide needed prevention and intervention efforts to reduce the tremendous negative public health and personal implications of substance misuse.